PROJECT DESCRIPTION: This SBIR Phase II proposal is intended to further develop a novel therapeutic approach to save the lives of severely injured trauma victims with hemorrhagic shock. Most trauma deaths result either from insufficient tissue perfusion due to excessive blood loss, or the development of inflammation, infection, and vital organ damage following resuscitation. Clinical management of hemorrhagic shock relies on massive and rapid infusion of fluids to maintain blood pressure. However, the majority of victims with severe blood loss do not respond well to fluid restoration. The development of effective strategies for resuscitation of traumatic blood loss, therefore, is urgently needed. The market potential for hemorrhage treatment is estimated at >$10 billion/year in the US alone. We have recently discovered that vascular responsiveness to adrenomedullin (AM), a newly-discovered potent vasoactive peptide, decreases after hemorrhage in the rat, which is markedly improved by its novel binding protein (i.e., AMBP-1). Treatment with rat AM plus AMBP-1 reduces tissue injury and inflammatory responses after hemorrhage and large volume resuscitation, suggesting that AM/AMBP-1 may be a beneficial treatment approach in human trauma. One obstacle hampering development of AM/AMBP-1 as a therapeutic agent for hemorrhagic shock is the potential immunogenicity of rat proteins in humans. Accordingly, the primary objective of our Phase I proposal was to determine the effect of human AM/AMBP-1 on hemorrhage- induced organ injury, inflammation, and mortality. We have achieved this milestone using a rodent model of severe hemorrhagic shock with fixed blood pressure. The results of the Phase I project demonstrated the efficacy of human AM/AMBP-1, and thereby established the technical merit and feasibility of the Phase II project. The dose-response study showed that the highest dose of human AM/AMBP-1 proposed in the Phase I project achieved a better protection after hemorrhage. However, the extremely high cost of commercial human AMBP-1 limits its further development. To overcome this obstacle, we have successfully isolated and purified AMBP-1 from human serum at a much lower cost. We therefore continue to hypothesize that administration of human AM/AMBP-1, even with low volume resuscitation, improves survival after severe blood loss. In this Phase II proposal, we plan to scale up the production of human AMBP-1, conduct additional efficacy studies determining the optimal protective dosage of human AM/AMBP-1 in hemorrhage, and perform pharmacokinetic characterization and toxicological evaluation. In order to advance the technology to clinical trials, the efficacy of human AM/AMBP-1 in more clinically relevant models of uncontrolled hemorrhage will be studied. Our ultimate goal is to develop the commercial utilization of human AM/AMBP-1 as a safe and effective resuscitation approach for the trauma victim with severe blood loss, especially for the use in combat casualty care at the far-forward battlefield setting.